Severe sepsis and more particularly at a further stage, septic shock, leading to multiple organ failure are major medical problems in critically ill patients and are the most common cause of death in medical and surgical intensive care unit (ICU) (Definition and epidemiology This L G, Dhainaut J F; in Septic Shock, Dhainaut J F, This L G, G Parked; Sunders 2000). Septic shock is a public health problem because of its frequency (500 000 to 700 000 new cases per year in the United States), and of it mortality Fate (around 45%). The systemic repercussion of septic shock is considered as the result of an uncontrolled and generalized immuno-inflammatory reaction. In the case of septic shock, that reaction results from a systemic host response to invasive infection. (From Celsus to Galen to Bone: The Illnesses, Syndromes, and Diseases of Acute Inflammation, Marshall J C, Aarts M A, in Yearbook of Intensive Care and Emergency Medicine, Vincent J L ed.; Springer Verlag, 2001; 3-12). This reaction leads to organ dysfunction and, at a further stage, organ failure.
The physiopathology of septic shock could be considered as a consequence of an overproduction of free radicals (Novelli, G. P., Role of free radicals in septic shock, J Physiol Pharmacol; 1997,48 (4): 517-527) (Zimmerman, J. J., Defining the role of oxyradicals in the pathogenesis of sepsis, Critical Care Medicine; 1995, 23, (4): 616-617) This does not contradict the usual diagrams concerning septic shock but points to free radicals as being directly responsible for cellular damages. The main origin of this deleterious overproduction of free radicals would be the activated polynuclear neutrophils adhering to the venous postcapillary segment (Bast, A.; Haenen, G. R.; Doelman, C. J., Oxidants and antioxidants: state of the art, Am J Med; 1991, 91, (3C): 2S−13S). In septic shock, nitric oxide is known to have a marked role. It appears early in septic shock. Its deleterious effects on the organism seems to be essentially mediated by peroxynitrite (ONOO—), formed during the simultaneous synthesis of NO by endothelium cells and superoxide anion by phagocytic cells, such as polymorphonuclears. Moreover, the endothelium is a particular target for peroxynitrite, Selenium may be an efficient treatment of septic shock in particular for increasing selenoprotein P concentration (Selenium and the “free” electron”—Selenium a trace to be followed in septic or inflammatory ICU patients, Forceville X, Intensive Care Medicine; 2001, 27: 16-18).
The early diagnosis and treatment of septic shock have to be conducted in a state of emergency. In man, at the present time, in the only phase III positive therapeutical trial in the treatment of the inflammatory reaction of septic shock, patients had to begin treatment within the first 24 hours of septic shock (Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis, Bernard G. R., Vincent J L, Laterre P F, New England Journal of Medicine; 2001). In fact, microcirculation endothelium is rapidly damaged during septic shock. The massive alterations of endothelium have a major physiopathological role in the consequences of septic shock and lead to organ failure (Sepsis/septic shock: Participation of the microcirculation: An abbreviated review, Hinshaw L B Critical Care Medicine 1996, 24 (6), 1072-1078).
There is a need in the art to have a relatively simple and reproducible biological marker to precisely identify septic shock patients in order to have reproducible epidemiological data, to define appropriate populations of patients to be included in sepsis trials, to identify populations of patients who might benefit from those therapies, and to monitor the evolution of septic shock under those therapies. Moreover that marker should ideally target the biological process or a biological process responsible for the manifestation of septic shock. “The search for such (a) marker(s) is an important priority for ongoing investigations” (From Celsus to Galen to Bone: The Illnesses, Syndromes, and Diseases of Acute Inflammation, Marshall J C, Aarts M A, in Yearbook of Intensive Care and Emergency Medicine, Vincent J L ed.; Springer Verlag, 2001; 3-12).
However, the diagnostic of sepsis and septic shock remains presently complex and depends on definitions that are based on clinical manifestations (Groeneveld, This, in Dhainaut 2000, Pg. 355). They characterize a subgroup of patients with systemic inflammatory response syndrome not only due to infection but also to diseases such as pancreatitis, extended burns, and polytrauma. For further details, see the American College of Chest Physicians and the Society of Critical Care Medicine, conference consensus, Chicago 1991 (The ACCP-SCCM consensus conference on sepsis and organ failure, Chest 1992; 101:1644-55), and the article by Marshall and Aarts (From Celsus to Galen to Bone: The Illnesses, Syndromes, and Diseases of Acute Inflammation, Marshall J C, Aarts M A in Yearbook of Intensive Care and Emergency Medicine, Vincent J L ed.; Springer Verlag, 2001; 3-12). Sepsis, severe sepsis and at a further stage septic shock may be due to infection associated or not with detected bacteremia due to bacteria, but also fungi or virus.
Septic shock is defined as a sepsis-induced hypoperfusion (i.e. systolic blood pressure <90 mmHg or a reduction of ≧40 mmHg from baseline) despite adequate fluid resuscitation along with the presence of perfusion abnormality that may include but are not limited to lactic acidosis, oliguria or an acute alteration in mental state. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that perfusion abnormalities are measured (Bone, 1992, ref. 2925) (Definition and epidemiology This L G, Dhainaut J F; in Septic Shock, Dhainaut J F, This L G, G Park ed.; Sunders 2000). This clinical definition established in the ACCP-SCCM consensus conference on sepsis and organ failure, Chicago, August 1991 remains the only valid one (The ACCP-SCCM consensus conference on sepsis and organ failure, Chest 1992; 101:1644-55).
Different markers of septic shock, and especially of its initial manifestation, have been proposed, but are non-specific and insensitive (Diagnosis: from clinical signs to haemodynamic evaluation, Groeneveld A B J, This G T; in Septic Shock, Dhainaut J F, This L G, G Park ed.; Sunders 2000). As activation of inflammatory pathways, including the cytokine network, is considered to play a major role in the pathogenesis of septic shock, cytokines have been extensively studied as a potential marker of septic shock (Cytokines and Anticytokines in the Pathogenesis of sepsis, van der Poll T, van Deventer S J H, Infectious disease Clinics of North America; 13 (2) 1999; 413-426). In comparison with other cytokines, IL-6 (a mixed pro- and anti-inflammatory cytokine) has been reported most consistently in the circulation of septic patients. However, IL-6 level shows considerable variation, and it is not possible to define a cut-off value to identify septic shock patients (Cytokines and Anticytokines in the Pathogenesis of sepsis, van der Poll T, van Deventer S JH, Infectious disease Clinics of North America; 13 (2) 1999; 413-426) Procalcitonin (PCT), C-reactive protein (CRP), leukocytosis, lactate concentration, coagulation parameters, and other parameters have also been proposed to identify septic shock patients (Diagnosis of sepsis: Novel and Conventional Parameters, Rheinhart K, Meisner M and Hartog C, Advances in sepsis, 2001; 42-51). However, though they seem to be useful parameters to improve the diagnosis and monitoring of septic shock, they cannot clearly identify septic shock patients due to their lack of specificity and the diagnosis of septic shock remains based on clinical parameters. (From Celsus to Galen to Bone: The Illnesses, Syndromes, and Diseases of Acute Inflammation, Marshall J C, Aarts M A, in Yearbook of Intensive Care and Emergency Medicine, Vincent J L ed.; Springer Verlag, 2001; 3-12). Presently, laboratory abnormalities can only be supportive for the diagnosis of sepsis and cannot prove the presence of septic shock. Taken together, abnormalities in hematological and chemical laboratory parameters may only constitute indicators of septic shock (Diagnosis: from clinical signs to haemodynamic evaluation, Groeneveld A B J, This G T; in Septic Shock, Dhainaut J F, This L G, G Park ed.; Sunders 2000). Each alone of this parameters carries little meaning. (Defining a Clinical Syndrome of Systemic inflammation, Vincent J L, Byl B, Sepsis, 200; 4:15-19).
Their is also an urgent need in the art to find a specific and reliable parameter to define septic shock patients. A precise definition of septic shock patients could allow an early diagnosis and a follow-up of septic shock. This parameter should ideally be closely related to the physiopathological process of septic shock (From Celsus to Galen to Bone: The Illnesses, Syndromes, and Diseases of Acute Inflammation, Marshall J C, Aarts M A, in Yearbook of Intensive Care and Emergency Medicine, Vincent J L ed.; Springer Verlag, 2001; 3-12).